Apolipoprotein E4 reduces evoked hippocampal acetylcholine release in adult mice

Abstract

Apolipoprotein E4 (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease. We utilized apoE4-targeted replacement mice (approved by the Tel Aviv University Animal Care Committee) to investigate whether cholinergic dysfunction, which increases during aging and is a hallmark of Alzheimer's disease, is accentuated by apoE4. This revealed that levels of the pre-synaptic cholinergic marker, vesicular acetylcholine transporter in the hippocampus and the corresponding electrically evoked release of acetylcholine, are similar in 4-month-old apoE4 and apolipoprotein E3 (apoE3) mice. Both parameters decrease with age. This decrease is, however, significantly more pronounced in the apoE4 mice. The levels of cholinacetyltransferase (ChAT), acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) were similar in the hippocampus of young apoE4 and apoE3 mice and decreased during aging. For ChAT, this decrease was similar in the apoE4 and apoE3 mice, whereas it was more pronounced in the apoE4 mice, regarding their corresponding AChE and BuChE levels. The level of muscarinic receptors was higher in the apoE4 than in the apoE3 mice at 4 months and increased to similar levels with age. However, the relative representation of the M1 receptor subtype decreased during aging in apoE4 mice. These results demonstrate impairment of the evoked release of acetylcholine in hippocampus by apoE4 in 12-month-old mice but not in 4-month-old mice. The levels of ChAT and the extent of the M2 receptor-mediated autoregulation of ACh release were similar in the adult mice, suggesting that the apoE4-related inhibition of hippocampal ACh release in these mice is not driven by these parameters. Keywords: acetylcholine release, Alzheimer's disease (AD), apolipoprotein E4 (apoE4), hippocampus. J. Neurochem. (2016) 136, 503-509. Cholinergic impairments are a hallmark of Alzheimer's disease (AD) (Craig et al. 2011). Genetic studies revealed that the allele e4 of apolipoprotein (APOE4 gene, apoE4 protein) is the most prevalent genetic risk factor for AD (Corder et al. 1993;Saunders et al. 1993). ApoE4 in AD and normal subjects is associated with biochemical cholinergic impairments (Reinvang et al. 2013). Furthermore, the response of apoE4-carrying AD patients (Braga et al. 2015) and normal controls (Pomara et al. 2004) to pharmacological cholinergic activation is impaired relative to corresponding subjects who express apolipoprotein E3 (apoE3), the AD benign isoform of this molecule. However, the extent to which apoE4 affects the release of acetylcholine (ACh) has not yet been determined.Transgenic mice have been prepared that express apoE4 or apoE3 under the regulation of either astrocytic or neuronal promoters, in addition to apoE-targeted replacement (TR) mice in which the endogenous mouse apoE was replaced by human apoE4 and apoE3 (Sullivan et al. 2011). Of these mice, the TR apoE mice have become the standard model in the field. Measurement of long-term potentiation (LTP) revealed a lower response in apoE4 TR mice ...

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